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1.
Placenta ; 34(9): 810-6, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23849932

RESUMO

BACKGROUND & AIMS: TGR5 (Gpbar-1) is a plasma membrane-bound bile acid receptor expressed in several tissues, including liver, intestine and brain. High levels of TGR5 mRNA have been detected in human and rodent placenta, however, localization of the TGR5 protein has not been studied in this tissue. We aimed at characterizing TGR5 expression in placental tissue and investigated the effect of bile acids and progesterone metabolites, which accumulate during intrahepatic cholestasis of pregnancy (ICP), on receptor expression and localization. METHODS: TGR5 mRNA levels and cell-specific localization were determined by quantitative PCR and immunofluorescence, respectively. RESULTS: In human term placentas, TGR5 was mainly localized in fetal macrophages and to a lower extent in trophoblasts. In placentas from ICP patients and pregnant rats with obstructive cholestasis a marked down-regulation of TGR5 mRNA expression was observed. However, the cell-specific distribution of the TGR5 protein was unaffected. Besides bile acids, progesterone and its metabolites (5α-pregnan-3α-ol-20-one/5α-pregnan-3ß-ol-20-one), which increase in serum during ICP, were able to dose-dependently activate TGR5. In addition, progesterone metabolites but not their sulfated derivatives nor taurolithocholic acid, significantly down-regulated TGR5 mRNA and protein expression in isolated human macrophages and a macrophage-derived cell line. CONCLUSION: Since fetal macrophages and trophoblast cells are exposed to changes in the flux of compounds across the placental barrier, the expression of TGR5 in these cells together with its sensitivity to bile acids and progesterone metabolites regarding receptor activity and mRNA expression suggest that TGR5 may play a role in the effect of maternal cholestasis on the placenta.


Assuntos
Colestase Intra-Hepática/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Macrófagos/metabolismo , Placenta/metabolismo , Complicações na Gravidez/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Trofoblastos/metabolismo , Animais , Ácidos e Sais Biliares/metabolismo , Células Cultivadas , Colestase Intra-Hepática/imunologia , Colestase Intra-Hepática/patologia , Modelos Animais de Doenças , Feminino , Genes Reporter , Células HEK293 , Humanos , Ativação de Macrófagos , Macrófagos/citologia , Macrófagos/imunologia , Macrófagos/patologia , Placenta/imunologia , Placenta/patologia , Gravidez , Complicações na Gravidez/imunologia , Complicações na Gravidez/patologia , Progesterona/análogos & derivados , Progesterona/metabolismo , Ratos , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Trofoblastos/imunologia , Trofoblastos/patologia
2.
Placenta ; 32(12): 1026-32, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22015023

RESUMO

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy specific liver disease associated with significant risk of fetal complications. It is hypothesised that the risk of adverse fetal outcomes relates to the toxic effects of bile acids, the levels of which are increased in both maternal and fetal serum. Human and rodent studies have shown that transplacental transfer of bile acids is impaired in ICP. Furthermore, the morphology of placentas from the rodent model of ICP is markedly abnormal, and is associated with increased expression of apoptotic markers and oxidative stress. Using placental tissue from ICP cases and normal pregnancies and cultured placental explant fragments we investigated the histological and molecular effects of cholestasis. We also examined the influence of ursodeoxycholic acid (UDCA) administration on these parameters. Here we report that ICP is associated with several morphological abnormalities of the placenta, including an increase in the number of syncytial knots, and that these can be reproduced in an in vitro (explant) model exposed to the bile acids taurocholic acid and taurochenodoexycholic acid. Furthermore, we demonstrate that ursodeoxycholic acid, a drug commonly used in the management of ICP, has a protective effect on placental tissue both in vivo and in vitro.


Assuntos
Colestase Intra-Hepática/patologia , Placenta/patologia , Complicações na Gravidez/patologia , Colestase Intra-Hepática/tratamento farmacológico , Feminino , Humanos , Fenótipo , Placenta/efeitos dos fármacos , Placenta/metabolismo , Gravidez , Complicações na Gravidez/tratamento farmacológico , Ácido Tauroquenodesoxicólico/farmacologia , Ácido Taurocólico/farmacologia , Ácido Ursodesoxicólico/uso terapêutico
3.
Placenta ; 32(7): 535-7, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21596433

RESUMO

Bile acids are the toxic end products of hepatic cholesterol metabolism. They are synthesised from early in gestation and excreted via the placenta. The mechanism for transplacental excretion of bile acids is not known. The gene and protein expression of the nuclear receptors responsible for hepatic bile acid metabolism and transport was studied in eight normal and fourteen cholestatic placentas, and in an ex vivo model. The expression of the nuclear receptor FXR and several of it's target genes and of PXR and CAR was found to be very low in both normal and cholestatic placenta.


Assuntos
Transportadores de Cassetes de Ligação de ATP/biossíntese , Colestase Intra-Hepática/metabolismo , Placenta/metabolismo , Complicações na Gravidez/metabolismo , Receptores Citoplasmáticos e Nucleares/biossíntese , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Esteroides/metabolismo , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Ácidos e Sais Biliares/metabolismo , Receptor Constitutivo de Androstano , Feminino , Expressão Gênica , Humanos , Fígado/metabolismo , Gravidez , Receptor de Pregnano X
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